This application for continuation of the Specialized Program of Research Excellence (SPORE) in Gastro-intestinal Cancer at The Johns Hopkins Medical Institutions supports a highly interactive, multidisciplinary program of translational research directed at reducing incidence of and mortality from colorectal and pancreatic cancer. The SPORE consists of 4 research programs with 8 projects built upon successful existing programs: Program 1 - Translational applications of molecular genetics for the early detection of colorectal and pancreatic cancer. Project 1A - Mutant genes in feces for early detection of colorectal neoplasms (Bernard Levin, M.D. Project 1B - New genetic markers for pancreatic cancer (Scott Kern, M.D.). Project 1C - Targets for screening in pancreatic neoplasia (Scott Kern, M.D.). Program 2 - New prognostic and diagnostic markers for colorectal and pancreatic cancer. Project 2 - Molecular markers for metastasis of colorectal cancer (Stanley Hamilton, M.D.). Program 3 - Prevention of colorectal and pancreatic cancer in genetically-destined patients by molecular genetic approaches. Project 3A - Genetic analysis of hereditary colorectal cancer syndromes (Kenneth Kinzler, Ph.D.). Project 3B - Agents and mechanisms of tumor prevention in the MIN model of familial adenomatous polyposis (Stanley Hamilton,M.D.). Project 3C - Markers for risk in familial pancreatic cancer (Ralph Hruban, M.D.). Program 4 - Novel therapies for pancreatic and colorectal cancer. Project 4 -Identification of T cell recognition targets in pancreatic adenocarcinomas (Elizabeth Jaffee, M.D.). Four cores support the research programs: Core l - SPORE administration and communication (Stanley Hamilton, M.D.). Core 2 - Human tissue resource and logistics (Stanley Hamilton, M.D.). Core 3 - Colorectal and pancreatic cancer patient registry (Francis Giardiello, M.D., and Ralph Hruban, M.D.). Core 4 - Biostatistics (Steven Goodman, M.D., Ph.D.). The SPORE includes a major Developmental Research Program (Bert Vogelstein, M.D.) for rapid funding of innovative projects and a Career Development Program (Stanley Hamilton, M.D.).